Guided therapy selection in rheumatoid arthritis using a molecular signature response classifier: an assessment of budget impact and clinical utility

BACKGROUND: Patients with moderate to severe rheumatoid arthritis (RA) can be treated with a range of targeted therapies following inadequate response to conventional synthetic disease-modifying antirheumatic drugs such as methotrexate. Whereas clinical practice guidelines provide no formal recommendations for initial targeted therapies, the tumor necrosis factor alpha inhibitor (TNFi) class is the prevalent first-line selection based on clinician experience, its safety profile, and/or formulary requirements, while also being the costliest. Most patients do not achieve adequate clinical response with a first-line TNFi, however. A molecular signature response classifier (MSRC) test that assesses RA-related biomarkers can identify patients who are unlikely to achieve adequate response to TNFi-class therapies. OBJECTIVE: To model cost-effectiveness of MSRC-guided, first-line targeted therapy selection compared with current standard care. METHODS: This budget impact analysis used data sourced from August to September 2020. The prevalence of each first-line targeted therapy was obtained using market intelligence from Datamonitor/Informa PLC Rheumatology Dashboard Forecast 2020, and the average first-year cost of treatment for each class was calculated using wholesale acquisition costs from IBM Micromedex RED BOOK Online. Average effectiveness for each class was based on manufacturer-reported ACR50 response rates (American College of Rheumatology adequate response criteria of 50% improvement at 6 months after therapy initiation). The impact of MSRC testing on first therapy selection was predicted based on a third party-generated decision-impact study that analyzed potential alterations in rheumatologist prescribing patterns after receiving MSRC test reports. Sensitivity analysis evaluated potential impacts of variation in first-year medication cost, adherence to MSRC report, and test price on the first-year cost of treatment. Cost for response (first-year therapy cost therapy divided by probability of achieving ACR50) was compared between standard care and MSRC-guided care. RESULTS: The estimated cost for first-year, standard-care treatment was $65,117, with 80% of patients initiating treatment with a TNFi. Cost for achieving ACR50 response was $177,046. After applying MSRC-guided patient stratification and therapy selection, the first-year cost was $56,543, net of test price, with 49.0% of patients initiating with a TNFi. First-year MSRC-guided care cost, including test price, was estimated at $117,103, a 33.9% improvement over standard care. Sensitivity analysis showed a net cost improvement for guided care vs standard care across all scenarios. Patients predicted to be inadequate TNFi responders, when modeled with lower-priced alternatives, were predicted to show increased ACR50 response rates. Those with MSRC test results indicating a first-line TNFi were predicted to show an ACR50 response rate superior to that for any other class. In this model, if implemented clinically, MSRC-guided care might save the US health care system more than $850 million annually and improve ACR50 by up to 31.3%. CONCLUSIONS: Precision medicine using MSRC-guided patient stratification and therapy selection may both decrease cost and improve efficacy of targeted RA therapies.

• Targeted RA therapies do not meet cost-effectiveness standards as defined by the Institute for Clinical and Economic Review.
• Molecular signature response classifier (MSRC) testing has been shown through multiple clinical studies to correctly identify patients who are unlikely to respond in a clinically meaningful way (defined as achieving an ACR50 response [American College of Rheumatology response criteria of 50% improvement within 6 months]) to the most prescribed-and costliest-first targeted therapy class, tumor necrosis factor alpha inhibitors (TNFis).

What this study adds
• This study estimated the cost of achieving ACR50 improvement in response using the current distribution of targeted therapy selection vs changes in therapy selection after MSRC-guided patient stratification. Patients predicted to have inadequate response to TNFi might move to less expensive alternative therapy classes and achieve higher rates of clinically meaningful response.
• Compared with current standard care, MSRC-guided therapy selection could save the health care system $8,575 per patient assessed and increase the probability of achieving an adequate response by 31.3%.
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes pain, swelling, stiffness, and progressive joint damage and affects approximately 0.5% to 1% of the population in developed countries. 1 The annual US cost of RA care is estimated to be $140 billion, according to the US Centers for Disease Control and Prevention, 2 highlighting a burden to the health care system. Approximately 70% of patients do not achieve adequate clinical response with their first treatment. 3 Therefore, patients often must undergo a time-consuming trial-and-error process with multiple medication classes, in accordance with the "treat-to-target" approach embraced by both the American College of Rheumatology (ACR) 4

and the European League Against
Rheumatism (EULAR). 5 This can have substantial negative effects on health care costs, control of disease progression, patient quality of life and productivity, and caregiver burden. 6 For patients with moderate to severe RA who do not achieve adequate response using conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate, subsequent options include a range of targeted biologic and small molecule therapies (targeted therapies). Currently, there are 5 first-line targeted therapy classes approved by the US Food and Drug Administration (FDA): tumor necrosis factor alpha inhibitors (TNFis), Janus kinase (JAK) inhibitors, interleukin (IL)-6 and IL-1 inhibitors, and T-cell costimulation modulators. These medications target different mechanistic pathways associated with RA.
Despite differences in effectiveness observed among these targeted therapy classes, with multiple studies showing that some JAK and IL-6 inhibitors are superior to TNFi therapies, 7-10 ACR clinical practice guidelines do not recommend one targeted therapy class over another, 4 so there currently exists no established first-line standard of care. However, many formularies mandate TNFi therapy for first-line use, and providers may have more experience and comfort with the TNFi safety profile. Consequently, most patients receive a TNFi as the first-line targeted therapy, with the remainder split between 7 other therapies across the 4 alternative classes. 11, 12 As of 2017, no approved targeted RA therapy had met typical standards for cost-effectiveness, as measured by cost per quality-adjusted life-year (QALY), according to the Institute for Clinical and Economic Review (ICER). 13 Despite no improvements in efficacy, the annual cost of TNFi treatment rose from 2017 to 2021. 13,14 Although a substantial proportion of patients do not have an adequate response to the first-line TNFi, and despite the lack of costeffectiveness, TNFi-class therapies remain prevalent.
Precision medicine tools have the potential to address the issue of delays in effective RA treatment and associated costs by helping to guide first-line targeted therapy selection. 3 EULAR clinical practice guidelines recognize the need for such tools to aid in stratifying patients to the most appropriate drug. 5 PrismRA is a laboratorydeveloped molecular signature response classifier (MSRC) test designed to predict the likelihood that a patient with moderate to severe RA will not respond adequately to a first-line TNFi therapy. It combines a patient's unique molecular signature, derived from interpreting 23 markers involved in RA biology. 15 The test has been clinically validated across multiple independent cohorts, with targeted therapy-naive patients who have an MSRC signal of TNFi therapy was obtained using market intelligence from Datamonitor/ Informa PLC Rheumatology Dashboard Forecast 2020, and the average first-year cost of treatment for each class was calculated using wholesale acquisition costs from IBM Micromedex RED BOOK Online. Average effectiveness for each class was based on manufacturerreported ACR50 response rates (American College of Rheumatology adequate response criteria of 50% improvement at 6 months after therapy initiation). The impact of MSRC testing on first therapy selection was predicted based on a third party-generated decision-impact study that analyzed potential alterations in rheumatologist prescribing patterns after receiving MSRC test reports. Sensitivity analysis evaluated potential impacts of variation in first-year medication cost, adherence to MSRC report, and test price on the first-year cost of treatment. Cost for response (first-year therapy cost therapy divided by probability of achieving ACR50) was compared between standard care and MSRC-guided care.

RESULTS:
The estimated cost for first-year, standard-care treatment was $65,117, with 80% of patients initiating treatment with a TNFi. Cost for achieving ACR50 response was $177,046. After applying MSRC-guided patient stratification and therapy selection, the first-year cost was $56,543, net of test price, with 49.0% of patients initiating with a TNFi. First-year MSRC-guided care cost, including test price, was estimated at $117,103, a 33.9% improvement over standard care. Sensitivity analysis showed a net cost improvement for guided care vs standard care across all scenarios. Patients predicted to be inadequate TNFi responders, when modeled with lower-priced alternatives, were predicted to show increased ACR50 response rates. Those with MSRC test results indicating a first-line TNFi were predicted to show an ACR50 response rate superior to that for any other class. In this model, if implemented clinically, MSRC-guided care might save the US health care system more than $850 million annually and improve ACR50 by up to 31.3%.

CONCLUSIONS:
Precision medicine using MSRC-guided patient stratification and therapy selection may both decrease cost and improve efficacy of targeted RA therapies.
polymorphisms, 10 RNA transcripts, and clinical features including the patient's sex, body mass index, and patient global assessment. The test report presents the likelihood of TNFi inadequate response on a continuous scale of 1 to 25 across 4 score categories (no signal, moderate, high, very high), with the probability of inadequate response increasing with MSRC score. Patients receiving a test result of "no signal" lack a signature indicative of inadequate response. This test is ordered by licensed providers, notably rheumatologists, before patients initiate first-line targeted therapies. Since the MSRC is a laboratory-developed test and regulated by Clinical Laboratory Improvement Amendments, FDA approval or clearance is not required. The MSRC is not a DNA test and is not indicated for diagnosing RA, monitoring disease activity, or assessing gene-drug interactions.

CANDIDATE THERAPY POPULATION
The number of US patients eligible to start new targeted therapy each year was estimated by reducing the annual number of newly diagnosed RA patients (41 per 100,000) 20 by the annual number who achieve ACR/EULAR-defined remission 18 on methotrexate (27%, based on internal analysis and previously published data 21 ). This resulted in 0.03% of participants in the US health care system who would be candidates for targeted therapy, or approximately 100,000 individuals.

FIRST-LINE PRESCRIBING RATES
Prescribing rates for current standard-care, first-line targeted therapies were obtained from market intelligence data (Datamonitor/Informa PLC Rheumatology Dashboard Forecast 2020, Informa PLC). The model of MSRC-guided prescribing rates for first-line targeted therapies was created using the results from 2 previously published studies. First, data from a previously published decision-impact study of 248 rheumatologists, conducted from May 28, 2020, through June 11, 2020, by a third-party provider (HealthiVibes, a division of CorEvitas, LLC), reported how providers might alter their prescribing patterns after receiving MSRC test results. 22 Next, the proportions of an MSRC-tested population that would have scores in each category (no signal, 53.0%; moderate, 5.0%; high, 15.0%; very high, 27.0%) were calculated from real-world data from a previously published clinical validation study that tested targeted therapy-naive RA patients who did not achieve adequate response to csDMARDs. 15 Finally, the probability of prescribing a given therapy class (TNFi, IL-6 inhibitor, JAK inhibitor, other, csDMARD) in each MSRC score category was derived by multiplying the estimated MSRC-guided physician selection rate for the therapy class by the proportion of the tested population having a score in that category.
nonresponse showing an up to 9 times lower likelihood of having an adequate response to TNFi therapy. 16 The aim of this budget impact analysis was to model the cost-effectiveness of incorporating this MSRC test into first-line RA targeted therapy selection by comparing the average cost for adequate response between test-guided patient stratification and therapy selection with the current standard of care.

Methods
The budget impact analysis was conducted using market intelligence data inputs sourced from August to September 2020, along with data from peer-reviewed publications reporting research approved by institutional review boards. The analysis used the following approach to model costeffectiveness of first-line targeted therapy selection for MSRC test-guided care vs standard care. Standard care was defined as clinician judgment, along with first-year prescribing rates estimated based on market intelligence (see "First-Line Prescribing Rates" section).
The analysis had 3 components: (1) estimating the average cost for 1 year of treatment for each approved targeted RA therapy; (2) predicting the average response rate for a patient's first targeted therapy based on manufacturerreported response scores, under standard care or when patient stratification and subsequent therapy selection are guided by MSRC test results; and (3) using average cost of care and response rate measures to calculate and compare the average cost for adequate response between the 2 treatment groups. Adequate response is defined as ACR50, the American College of Rheumatology response criteria of 50% improvement within 6 months after therapy initiation. [17][18][19] The study design is depicted in Supplementary  Figure 1 (available in online article).
Because this budget impact analysis did not contain novel studies involving human participants, it did not meet the definition of human subjects research according to US Department of Health and Human Services 45 Code of Federal Regulations Part 46.

MOLECULAR SIGNATURE RESPONSE CLASSIFIER TESTING
The MSRC test (PrismRA; Scipher Medicine Corporation) is a clinically validated test that interprets biomarkers found in RA biology using next-generation sequencing and network medicine to identify RA patients who possess a molecular signature predictive of inadequate response to TNFi therapies. 15,16 "Inadequate response" is defined as the failure to achieve the ACR50 threshold of response at 6 months. The test evaluates 23 biomarkers, including 8 single nucleotide

FIRST-YEAR COST OF TREATMENT
First-year cost of treatment for medications in each targeted therapy class were estimated using the first-year prescribing rate for each medication (number of units per dose and recommended dosage frequency per annum) and wholesale acquisition cost (WAC). Data inputs to the cost calculation were sourced from IBM Micromedex Red Book Online (IBM). This calculation included cost of the medication only, without other components of care.

RESPONSE RATES
Predicted response rate for standard-care treatment was calculated using effectiveness data collected from drug manufacturer publications and expressed as the ACR50 response rate. To estimate the overall treatment response rate for MSRC-guided therapy selection, the standard-care ACR50 response rate for each targeted therapy class was applied to the modeled proportion of patients who were predicted to move from a TNFi to an alternative option based on MSRC score category.
This patient stratification and subsequent shift to non-TNFi options was modeled to eliminate most of the inadequate responders from the TNFi cohort, leaving only those patients with an MSRC result of "no signal"-or those patients who were, in effect, predicted TNFi responders. When inadequate responders were removed from the TNFi cohort and the remaining patient group was enriched with more predicted responders, the ACR50 response rate was expected to increase.
The physician decision-impact study indicated that not all patients with an MSRC result of "no signal" would be removed from the TNFi group. Some rheumatologists indicated that after their patients received a result of "no signal," rather than starting a biologic, they would continue treating patients with csDMARDs in order to maximize that treatment modality. The model assumed that rheumatologists eventually would employ treat-to-target methods and shift those patients from csDMARDs to a JAK inhibitor or IL-6 inhibitor or other targeted therapy, 4,5 should no adequate response occur after 3 to 6 months, 23 and the response rate should be similar to the average ACR50 response rate for targeted therapy.

SENSITIVITY ANALYSIS
In this model, there remained uncertainty in 3 variables: (1) first-year targeted therapy medication cost; (2) MSRC test price; and (3) adherence to the MSRC test result recommendation in targeted therapy prescribing. To account for this uncertainty, an equal-probability assessment was performed using these variables, providing 3 scenarios for each. First-year targeted therapy medication cost scenarios

PRESCRIBING DISTRIBUTION INFORMED BY MSRC RESULTS VS STANDARD CARE
Modeled initial therapy selection based on MSRC-guided prescribing is shown in Table 2. Predicted MSRC-guided therapy class selection rates for each score category, based on physician-indicated choices, are shown at left. The probability that each therapy class will be selected using MSRC test results to guide decisions, based on the proportion of scores expected in each category across the tested population, is shown at right. The overall probability of prescribing included estimated cost net of rebates (low-end), WAC prices (mid-range), and estimates for average wholesale price (AWP) (high-end), sourced from IBM Micromedex Red Book Online and the 2017 ICER report "Targeted Immune Modulators for Rheumatoid Arthritis: Effectiveness & Value." 13 Scenarios for MSRC test price, which will vary based on insurance coverage and payer contracts, were assigned low-end ($1,250), mid-range ($2,250), and high-end ($3,100) values. Scenarios for adherence to the MSRC test result recommendation, which can vary based on physician preference and formulary requirements, included "mandated" adherence (100% adherence to the test result recommendation); "study" adherence, based on the published physician decision-impact study 22 ; and "TNFi-restricted" adherence, which represents the "study" adherence and adjusted for the percentage of lives that would be formulary-required to receive a TNFi, regardless of MSRC test result (19%; data sourced from Managed Markets Insight & Technology, LLC) The impact of all combinations of the 3 variables was applied to the primary analysis to produce a range of possible cost savings per tested patient.

COST FOR RESPONSE
The cost for response was calculated for standard care by dividing the annual cost of the first targeted therapy by the probability of achieving an adequate ACR50 response. For MSRC-guided care, cost for response was calculated similarly but also accounted for the average net savings from the sensitivity analysis, which factored in test price. For better clarity, this model did not incorporate medication changes   Table 1). Thus, the results of the primary analysis remain robust. When applied to the annual candidate therapy population of 100,000 individuals in the United States, these cost savings could amount to more than $850 million.

COST FOR RESPONSE
The calculation of the total cost for the first year of treatment for MSRC-guided selection is detailed in Supplementary Table 2 (available in online article). Across all targeted therapy classes and score categories, the average cost for the first year of MSRC-guided treatment was estimated at $56,543 per patient, which represents a savings of $8,575 per tested patient when compared with standard care ($65,117; Table 1). Applying the cost for the first year of targeted therapy to response rates for therapy selection produced the average cost for response. Table 5 summarizes the comparison of the first-year cost for response between in prescribing from standard care, are shown in Table 3. Overall, the treatment response rate for MSRC-guided patients was estimated to be 48.3%, representing a 31.3% improvement over the standard-care rate of 36.8% (Table 1). Because some patients with moderate, high, or very high category scores would continue with a TNFi due to provider or patient preference, the fraction of the guided patient cohort who would be prescribed TNFi therapies would have an ACR50 response of 53.6%, a substantial increase over the 35.8% estimated for standard-care TNFi response (Table 1). No notable differences in ACR50 response rates were noted between MSRC-guided and standard-care use estimates for JAK inhibitor or IL-6 inhibitor therapies. Table 4 shows the predicted ACR50 response rates for TNFi therapy by MSRC score category and prescribing rate. The 5 TNFi therapy classes were estimated to share a narrow ACR50 range, and the weighted average ACR50 response rate for all combined was predicted to be 35.8%, which is identical to the combined TNFi response rate for standard care (Table 1). Individuals with an MSRC score in the "no signal" category were predicted to have the lowest likelihood of inadequate response to TNFi therapies and therefore were most likely to benefit from this therapy class. If the 53.1% of the testing population who were predicted to have an MSRC result of "no signal" received TNFi therapy, the ACR50 response would be estimated at 60.6%, making it the most effective therapy class of all available options for these patients. When inadequate responders were removed from the TNFi cohort and the remaining patient group was enriched with more predicted responders, the original ACR50 response rate of 35.8% shifted to the recalculated rate of 60.6% (Table 4). For patients in the "no a TNFi class therapy using MSRC guidance, 49.0% (Table 2), is substantially lower than the current first-line prevalence estimate, 80.0%, for standard care (Table 1). Conversely, the probabilities of prescribing JAK inhibitor (20.2%) and IL-6 inhibitor therapies (13.0%) increased relative to current estimates for standard care. With a focus on cost-effectiveness, the probability of prescribing an IL-6 inhibitor was modeled at 30.6% (Table 3).

RESPONSE RATES
Predicted ACR50 response rates for MSRC-guided therapy class selection across all score categories combined, based on predicted shifts   13 ICER puts cost-effectiveness standards between $50,000 and $150,000 per QALY achieved; none of the targeted RA treatments available at the time met this standard. The recommendation from ICER was to negotiate lower prices for the medications to ensure acceptable cost-effectiveness; however, prices have only increased. If precision-guided therapy selection has the same impact on cost per QALY as it does on cost for response-a reduction of 33.9%-the cost per QALY would be $140,502, making the treatment of advanced RA cost effective.
Patients who do not respond to initial targeted therapy have a permanent negative shift in their health trajectory, based on the likelihood of disease progression over the extended duration of medication trial-and-error. [24][25][26] Most patients with inadequate response to their first TNFi will move to a second TNFi therapy, despite this approach being shown to be less effective than moving to a non-TNFi. 27 This practice, called TNFi cycling, persists in most TNFiexperienced patients, 5,28 despite being contraindicated by ACR clinical practice guidelines. 4 The average time that patients remain in this therapy class is over 2 years. 29 While MSRC-guided therapy and standard care. With an average response rate of 36.8%, the standard-care cost for response was calculated to be $177,046 per patient. In comparison, with an average ACR50 response of 48.3%, the cost for response for MSRC-guided treatment was estimated at $117,103 per patient.

Discussion
This analysis built a budget impact model for MSRC-guided medication selection based on rheumatologist-predicted prescribing decisions for initial targeted RA therapies 22 combined with clinical and cost-effectiveness outcomes resulting from clinical implementation of the test. 3 By applying datasets from these previous studies, we estimated that a precision medicine-based approach using a molecular signature test to stratify patients and subsequently inform initial therapy selection can increase clinical response rates and reduce the cost for response. Substantial budgetary improvement can be achieved from selection of alternative FDA-approved therapies for patients predicted by the MSRC test to have inadequate response to TNFi-class therapies while also initiating TNFi therapies per standard care for individuals lacking the inadequate response signature. The sensitivity analysis, which accounted for scenarios that were both more relaxed and more stringent than the primary analysis, suggested that improvement can be realized   this assessment of cost-effectiveness is for the first year only, it is possible that longer-term improvement in savings could be achieved using a precision medicine-guided approach that includes moving to an alternative FDA-approved therapy after inadequate response with the first TNFi.

LIMITATIONS
This study has the following limitations to consider. First, the resulting cost savings will vary based on the price difference between the TNFi and that of the alternative therapy used; these will differ based on formulary policies and the use of biosimilars. Second, the ACR50 response used in the analysis for inadequate responseidentified patients who move on to an alternative treatment may be lower or higher than that of the FDA trial cohort for the second treatment. To date, there are insufficient data to show noninferiority or superiority.
Finally, this budget impact analysis relies on estimates that will vary based on real-world differences in medication costs, clinician practice, and formulary requirements. These variations exist, but overall trends for these components of the calculation have changed little over time.
Overall, the results of this analysis provide a foundation for future costeffectiveness studies that incorporate real-world data sources for MSRC test result recommendation adherence in first-line targeted therapy prescribing and ACR50 response rates.

Conclusions
MSRC testing represents a potential precision medicine decision tool to further target biologic and small molecule therapy choice in RA. Precision medicine in the form of MSRC testing has the potential to decrease cost and improve the efficacy of targeted RA therapy. Patients who initially